Current Aspects of Clonal Hematopoiesis: Implications for Clinical Diagnosis

Abstract

The broad dissemination of next-generation sequencing capability has increased recognition of clonal hematopoiesis in various clinical settings. In hematologically normal individuals, somatic mutations may occur at an increasing frequency with age in genes that are also commonly mutated in overt myeloid malignancies such as AML and MDS (e.g., DNMT3A, TET2, and ASXL1). This is referred to as clonal hematopoiesis of indeterminate potential (CHIP) and is a benign state; however, it carries a risk of progression to hematologic malignancy as well as mortality primarily because of increased cardiovascular events. In clinical settings, clonal hematopoiesis may be observed in cytopenic patients who do not otherwise meet the criteria for hematologic malignancy, a condition referred to as clonal cytopenias of undetermined significance (CCUS). Distinguishing CCUS from overt MDS or other myeloid neoplasms can be challenging because of the overlapping mutational landscape observed in these conditions. Genetic features that could be diagnostically helpful in making this distinction include the number and biological function of mutated genes as well as the observed variant allele frequency. A working knowledge of clonal hematopoiesis is essential for the diagnosis and clinical management of patients with hematologic conditions. This review describes the key characteristics of clonal hematopoiesis with particular focus on implications for differential diagnosis in patients with CHIP, idiopathic cytopenia, CCUS, and myeloid malignancy.

Keywords: Clonal cytopenias of undetermined significance; Clonal hematopoiesis; Clonal hematopoiesis of indeterminate potential; Idiopathic cytopenias of undetermined significance.

Fig. 1. Venn diagram showing the relationship between idiopathic cytopenias of undetermined significance (ICUS), clonal cytopenia of undetermined significance (CCUS), clonal hematopoiesis of indeterminate potential (CHIP), and myeloid malignancy. Patients with cytopenias without clonality are designated as ICUS, whereas patients with clonality without significant cytopenias are designated as CHIP. Patients with both cytopenia(s) and clonality are designated as CCUS. A subset of patients within this group will have morphological features diagnostic of myeloid malignancy; such features include significant dysplasia (≥10% dysplasia within one or more cell lineages), with or without increased blasts, and with or without other morphological atypia.